Triazolophthalazines

ABSTRACT

The compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     in which R1, R2 and R3 have the meanings as given in the description are novel effective PDE2 inhibitors.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel triazolophthalazine derivatives, whichcan be used in the pharmaceutical industry for the production ofpharmaceutical compositions.

KNOWN TECHNICAL BACKGROUND

Triazolophthalazines are known from prior art. For example, EP85840,WO98/04559, WO98/50385, WO99/06407 (corresponding to U.S. Pat. No.6,313,125), WO02/083140, WO00/26218 (corresponding to U.S. Pat. No.6,525,055), EP0728759 (corresponding to U.S. Pat. No. 6,001,830); J.Med. Chem., (1988), 31, 1115-1123; J. Med. Chem., (2004), 47, 1807-1822,and J. Med. Chem., (2004), 47, 2176-2179 describe triazolophthalazineswith various substitution patterns.

But, however, anilino-substituted triazolophthalazine derivatives in themeaning of the present invention have never been disclosed therein.

WO01/47929 describes triazolotriazinones with PDE2 inhibiting activity.

Yet however, triazolophthalazine derivatives have never been describedas PDE2-inhibitors.

DESCRIPTION OF THE INVENTION

It has now been found that the novel triazolophithalazine derivatives,which are described in greater details below, have surprising andparticularly advantageous properties.

The invention thus relates to compounds of formula I

in which

-   -   R1 is —U-A, in which    -   U is a direct bond, or methylene (—CH₂—),    -   A is phenyl, pyridinyl, thiophenyl, or R11- and/or        R111-substituted phenyl, in which    -   R11 is 1-4C-alkyl, halogen, trifluoromethyl, hydroxyl,        1-4C-alkoxy, completely or predominantly fluorine-substituted        1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl, morpholino, or        di-1-4C-alkylamino,    -   R111 is 1-4C-alkoxy, halogen, hydroxyl, or 1-4C-alkyl,    -   R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, phenyl-1-4C-alkoxy,        phenoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, halogen,        trifluoromethyl, nitro, phenyl, R21-substituted phenyl,        completely or predominantly fluorine-substituted 1-4C-alkoxy,        1-4C-alkylthio, cyano-1-4C-alkyl, or —N(R22)R23, in which    -   R21 is 1-4C-alkoxy, halogen or 1-4C-alkyl,    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, in which    -   Het1 is optionally substituted by R24, and is a 3- to 7-membered        monocyclic fully saturated heterocyclic ring radical comprising        the nitrogen atom, to which R22 and R23 are bonded, and        optionally one further heteroatom selected from nitrogen, oxygen        and sulphur, in which    -   R24 is 1-4C-alkyl,    -   R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,

and the salts of these compounds.

1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, and, particularly, the ethyl and methyl radicals.

Halogen within the meaning of the present invention is iodine or, inparticular, bromine, chlorine or fluorine.

1-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and, particularly, theethoxy and methoxy radicals.

1-4C-Alkoxycarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkoxy radicals is bonded. Examples are themethoxycarbonyl (CH₃O—C(O)—) and the ethoxycarbonyl (CH₃CH₂O—C(O)—)radical.

3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of whichcyclopropylmethoxy and cyclopentylmethoxy are to be emphasized.

3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and cyclo-heptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

Completely or predominantly fluorine-substituted 1-4C-alkoxy is, forexample, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the1,2,2-trifluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy,the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxyradical, of which the difluoromethoxy radical is preferred.“Predominantly” in this connection means that more than half of thehydrogen atoms of the 1-4C-alkoxy groups are replaced by fluorine atoms.

Di-1-4C-alkylamino stands for an amino group, which is substituted bytwo different or two identical of the abovementioned 1-4C-alkylradicals. Examples are the dimethylamino, the diethylamino and thediisopropyl radical.

Di-(1-4C-alkoxy)-phenyl stands for a phenyl radical, which issubstituted at any possible positions by two of the abovementioned1-4C-alkoxy radicals, which may be the same or different.

Phenyl-1-4C-alkoxy stands for one of the abovementioned 1-4C-alkoxyradicals, which is substituted by the phenyl radical. Examples which maybe mentioned are the benzyloxy and the phenethoxy radical.

Cyano-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals, which is substituted by the cyano group. Examples which may bementioned are the cyanomethyl and the 2-cyanoethyl radical.

4N-(1-4C-Alkyl)piperazin-1-yl stands for a piperazine-1-yl radical whichis substituted at its nitrogen atom in the 4-position by one of theabovementioned 1-4C-alkyl radicals, such as e.g.4N-methyl-piperazin-1-yl.

1-4C-Alkylthio represents radicals which, in addition to the sulfuratom, contain one of the abovementioned 1-4C-alkyl radicals. Exampleswhich may be mentioned are the butylthio, propylthio and preferably theethylthio and methylthio radicals.

In the meaning of the present invention, it is to be understood, that,when two structural portions of the compounds according to thisinvention are linked via a constituent which has the meaning “bond”,then said two portions are directly attached to another via a singlebond.

Het1 is optionally substituted by R24, and is a 3- to 7-memberedmonocyclic fully saturated heterocyclic ring radical comprising thenitrogen atom, to which R22 and R23 are bonded, and optionally onefurther heteroatom selected from nitrogen, oxygen and sulphur.

In an embodiment, Het1 stands for a 3- to 7-membered monocyclic fullysaturated heterocyclic ring radical comprising the nitrogen atom, towhich R22 and R23 are bonded, and optionally one further heteroatomselected from NH, N(R24), oxygen and sulphur.

Het1 may include, for example, without being restricted thereto,aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,homopiperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yland homopiperazin-1-yl.

As further examples for Het1 according to this invention may bementioned, without being restricted thereto, R24-substituted derivativesof the abovementioned exemplary Het1 radicals, such as e.g.4N-(R24)-piperazin-1-yl or 4N-(R24)-homopiperazin-1-yl.

Illustratively, as exemplary suitable Het1 radical may be mentioned,without being restricted thereto, 4N-(1-4C-alkyl)-piperazin-1-yl, suchas e.g. 4N-methyl-piperazin-1-yl, or, particularly, morpholin-4-yl.

The heterocyclic groups mentioned herein refer, unless otherwisementioned, to all of the possible isomeric forms thereof.

The heterocyclic groups mentioned herein refer, unless otherwise noted,in particular to all of the possible positional isomers thereof. Suchas, for example, the terms pyridyl or pyridinyl, alone or as part ofanother group, include pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, orthe term thiophenyl includes thiophen-2-yl and thiophen-3-yl.

Constituents, which are substituted as stated herein, may besubstituted, unless otherwise noted, at any possible position.

The heterocyclic groups mentioned herein may be substituted by theirgiven substituents, unless otherwise noted, at any possible position,such as e.g. at any substitutable ring carbon or ring nitrogen atom.

Unless otherwise noted, any heteroatom of a heterocyclic ring withunsatisfied valences mentioned herein is assumed to have the hydrogenatom(s) to satisfy the valences.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

The substituents R2 and R3 of compounds of formula I can be attached inthe ortho, meta or para position with respect to the binding position inwhich the phenyl ring is bonded to the amino group, whereby preferenceis given to the attachment in the meta or para position.

Suitable salts for compounds according to this invention—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerableinorganic and organic acids and bases customarily used in pharmacy.Those suitable are, on the one hand, water-insoluble and, particularly,water-soluble acid addition salts with acids such as, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonicacid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

On the other hand, salts with bases are—depending on substitution—alsosuitable. As examples of salts with bases are mentioned the lithium,sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium,meglumine or guanidinium salts, here, too, the bases being employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothis invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds according to thisinvention as well as their salts may contain, e.g. when isolated incrystalline form, varying amounts of solvents. Included within the scopeof the invention are therefore all solvates and in particular allhydrates of the compounds according to this invention as well as allsolvates and in particular all hydrates of the salts of the compoundsaccording to this invention.

Compounds according to this invention worthy to be mentioned are thosecompounds of formula I, in which

-   -   R1 is —U-A, in which    -   U is a direct bond, or methylene (—CH₂—),    -   A is phenyl, pyridinyl, thiophenyl, di-(1-4C-alkoxy)-phenyl, or        R11-substituted phenyl, in which    -   R11 is 1-4C-alkyl, halogen, trifluoromethyl, hydroxyl,        1-4C-alkoxy, completely or predominantly fluorine-substituted        1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl, morpholino, or        di-1-4C-alkylamino,    -   R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, phenyl-1-4C-alkoxy,        phenoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, halogen,        phenyl, R21-substituted phenyl, completely or predominantly        fluorine-substituted 1-4C-alkoxy, 1-4C-alkylthio,        cyano-1-4C-alkyl, or —N(R22)R23, in which    -   R21 is 1-4C-alkoxy, halogen or 1-4C-alkyl,    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, in which    -   Het1 is a 3- to 7-membered monocyclic fully saturated        heterocyclic ring radical comprising the nitrogen atom, to which        R22 and R23 are bonded, and optionally one further heteroatom        selected from N(R24), oxygen or sulphur, in which    -   R24 is 1-4C-alkyl,    -   R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,

and the salts of these compounds.

Compounds according to this invention more worthy to be mentioned arethose compounds of formula I, in which

-   -   R1 is —U-A, in which    -   U is a direct bond, or methylene (—CH₂—),    -   A is phenyl, pyridinyl, thiophenyl, dimethoxyphenyl, or        R11-substituted phenyl, in which    -   R11 is methyl, tertbutyl, chlorine, fluorine, bromine,        trifluoromethyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy,        phenoxy, methoxycarbonyl, morpholino, or dimethylamino,    -   R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, phenyl-1-4C-alkoxy,        phenoxy, halogen, phenyl, R21-substituted phenyl, completely or        predominantly fluorine-substituted 1-4C-alkoxy, 1-4C-alkylthio,        cyano-1-4C-alkyl, or —N(R22)R23, in which    -   R21 is 1-4C-alkoxy,    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, in which    -   Het1 is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,        thiomorpholin-4-yl, or 4N-(1-4C-alkyl)-piperazin-1-yl,    -   R3 is hydrogen or 1-4C-alkoxy,

and the salts of these compounds.

Compounds according to this invention in particular worthy to bementioned are those compounds of formula I, in which

-   -   R1 is —U-A, in which    -   U is a direct bond, or methylene (—CH₂—),    -   A is phenyl, or R11-substituted phenyl, in which    -   R11 is methyl, chlorine, fluorine, bromine, trifluoromethyl,        hydroxyl, methoxy, phenoxy, methoxycarbonyl, or dimethylamino,

whereby in particular

-   -   A is 4-methoxy-phenyl, 2-methoxy-phenyl, 2-bromo-phenyl,        4-bromo-phenyl, 2-fluoro-phenyl, 2-(trifluoromethyl)-phenyl,        3-methoxy-phenyl, 3-bromo-phenyl, 3-fluoro-phenyl, or        3-(trifluoromethyl)-phenyl;    -   R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, phenyl-1-4C-alkoxy,        phenoxy, halogen, phenyl, R21-substituted phenyl, completely or        predominantly fluorine-substituted 1-4C-alkoxy, 1-4C-alkylthio,        cyano-1-4C-alkyl, or —N(R22)R23, in which    -   R21 is 1-4C-alkoxy,    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, in which    -   Het1 is morpholin-4-yl, or 4N-(1-4C-alkylypiperazin-1-yl,    -   R3 is hydrogen or 1-4C-alkoxy,

and the salts of these compounds.

Compounds of formula I according to claim 1, in which

-   -   R1 is —U-A, in which    -   U is a direct bond, or methylene (—CH₂—),    -   A is phenyl, 4-methoxy-phenyl, 2-methoxy-phenyl,        2-hydroxy-phenyl, 2-bromo-phenyl, 4-bromo-phenyl,        2-fluoro-phenyl, 2-(trifluoromethyl)-phenyl, 2-methyl-phenyl,        3-methoxy-phenyl, 3-bromo-phenyl, 3-fluoro-phenyl,        2-dimethylamino-phenyl, methoxycarbonyl, phenoxy, or        3-(trifluoromethyl)-phenyl    -   R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, phenyl-1-4C-alkoxy,        phenoxy, halogen, phenyl, R21-substituted phenyl, completely or        predominantly fluorine-substituted 1-4C-alkoxy, 1-4C-alkylthio,        cyano-1-4C-alkyl, or —N(R22)R23, in which    -   R21 is 1-4C-alkoxy,    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, in which    -   Het1 is morpholin-4-yl, or 4N-(1-4C-alkyl)-piperazin-1-yl,    -   R3 is hydrogen or 1-4C-alkoxy,

and the salts of these compounds.

Compounds according to this invention in more particular worthy to bementioned are those compounds of formula I, in which

-   -   R1 is —U-A, in which    -   U is a direct bond,    -   A is phenyl, or R11-substituted phenyl, in which    -   R11 is fluorine, bromine, trifluoromethyl, or methoxy,

whereby in particular

-   -   R1 is 4-methoxy-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl,        2-bromo-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2-fluoro-phenyl,        3-fluoro-phenyl, 2-(trifluoromethyl)-phenyl, or        3-(trifluoromethyl)-phenyl,

and whereby in more particular

-   -   R1 is 4-methoxy-phenyl, or 2-bromo-phenyl;    -   R2 is hydrogen, methyl, methoxy, ethoxy, benzyloxy, chlorine,        phenoxy, phenyl, 4-methoxy-phenyl, trifluoromethoxy,        difluoromethoxy, methylthio, cyanomethyl, or —N(R22)R23, in        which    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, in which    -   Het1 is morpholin-4-yl, or 4N-methyl-piperazin-1-yl,    -   R3 is hydrogen, methoxy or ethoxy,

and the salts of these compounds.

Compounds of formula I according to claim 1, in which

-   -   R1 is 4-methoxy-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl,        2-bromo-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2-fluoro-phenyl,        3-fluoro-phenyl, 2-(trifluoromethyl)-phenyl, or        3-(trifluoromethyl)-phenyl;    -   R2 is hydrogen, methyl, methoxy, ethoxy, benzyloxy, chlorine,        phenoxy, phenyl, 4-methoxy-phenyl, trifluoromethoxy,        difluoromethoxy, methylthio, cyanomethyl, or —N(R22)R23, in        which    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, in which    -   Het1 is morpholin-4-yl, or 4N-methyl-piperazin-1-yl,    -   R3 is hydrogen, methoxy or ethoxy,

and the salts of these compounds.

Compounds of formula I according to claim 1, in which

-   -   R1 is phenyl, 2-hydroxy-phenyl, 4-phenoxy-phenyl,        3-methoxy-carbonyl-phenyl, 4-methoxy-carbonyl-phenyl,        4-morpholin-4-yl-phenyl, 4-methoxy-benzyl,    -   R2 is —N(R22)R23, in which R22 and R23 together and with        inclusion of the nitrogen atom, to which they are attached, form        a heterocyclic ring Het1, which is morpholin-4-yl,    -   R3 is hydrogen,

and the salts of these compounds.

Compounds of formula I according to claim 1, in which

-   -   R1 is 4-methoxy-phenyl,    -   R2 is hydrogen, methyl, methoxy, ethoxy, phenyl-methoxy,        phenoxy, chloro, bromo, R21-substituted phenyl,        trifluoromethoxy, difluoromethoxy, methylthio, cyano-1-4C-alkyl,        or —N(R22)R23, in which    -   R21 is methoxy,    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, which is        morpholin-4-yl, or 4N-methyl-piperazin-1-yl,    -   R3 is hydrogen,

and the salts of these compounds.

Compounds of formula I according to claim 1, in which

-   -   R1 is 4-methoxy-phenyl,    -   R2 and R3 is methoxy or ethoxy.

and the salts of these compounds.

A special interest in the compounds according to this invention refersto those compounds of formula I which are included—within the scope ofthis invention—by one or, when possible, by more of the followingspecial embodiments:

A special embodiment (embodiment 1) of the compounds according to thepresent invention refers to those compounds of formula I, in which

-   -   U is a direct bond, and    -   A is phenyl, or R11-substituted phenyl.

Another special embodiment (embodiment 2) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   U is a direct bond, and    -   A is pyridinyl or thiophenyl, such as e.g. pyridin-4-yl.

Another special embodiment (embodiment 3) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   U is methylene, and    -   A is phenyl, or R11-substituted phenyl.

Another special embodiment (embodiment 4) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   U is methylene, and    -   A is pyridinyl or thiophenyl, such as e.g. thiophen-2-yl.

Another special embodiment (embodiment 5) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R1 is (4-methoxy-phenyl)-methyl, or 4-methoxy-phenyl.

Another special embodiment (embodiment 6) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R1 is 4-methoxy-phenyl.

Another special embodiment (embodiment 7) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R1 is (4-methoxy-phenyl)-methyl, 2-hydroxy-phenyl, phenyl,        3-methoxycarbonyl-phenyl, or 4-methoxy-phenyl, 2-methoxy-phenyl,        4-bromo-phenyl, 2-bromo-phenyl, 2-fluoro-phenyl, or        2-(trifluoromethyl-phenyl, or 2-chloro-phenyl, 4-bromo-phenyl,        2-methyl-phenyl.

Another special embodiment (embodiment 8) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R1 is 4-methoxy-phenyl, 2-methoxy-phenyl, 4-bromo-phenyl,        2-bromo-phenyl, 2-fluoro-phenyl, or 2-(trifluoromethyl)-phenyl.

Another special embodiment (embodiment 9) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R1 is 2-bromo-phenyl.

Another special embodiment (embodiment 10) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R2 is methyl, methoxy, ethoxy, benzyloxy, chlorine, phenoxy,        phenyl, 4-methoxy-phenyl, trifluoromethoxy, difluoromethoxy,        methylthio, cyanomethyl, or —N(R22)R23, in which    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, in which    -   Het1 is morpholin-4-yl, or 4N-methyl-piperazin-1-yl, and    -   R3 is hydrogen.

Another special embodiment (embodiment 11) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R2 is methoxy, ethoxy, phenoxy, cyanomethyl, or —N(R22)R23, in        which    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, in which    -   Het1 is morpholin-4-yl, or 4N-methyl-piperazin-1-yl, and    -   R3 is hydrogen.

Another special embodiment (embodiment 11) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R2 is attached in the meta position with respect to the binding        position in which the phenyl ring is bonded to the amino group        of the triazolophthalazine scaffold, and    -   R3 is attached in the meta or para position with respect to the        binding position in which the phenyl ring is bonded to the amino        group of the triazolophthalazine scaffold.

Another special embodiment (embodiment 14) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R2 is attached in the para position with respect to the binding        position in which the phenyl ring is bonded to the amino group        of the triazolophthalazine scaffold, and    -   R3 is attached in the meta position with respect to the binding        position in which the phenyl ring is bonded to the amino group        of the triazolophthalazine scaffold.

A special group of the compounds according to the present inventionrefers to those compounds of formula I, in which

-   -   R1 is 4-methoxy-phenyl, 2-methoxy-phenyl, 4-bromo-phenyl,        2-bromo-phenyl, 2-fluoro-phenyl, or 2-(trifluoromethyl)-phenyl,    -   R2 is attached in the para or meta position with respect to the        binding position in which the phenyl ring is bonded to the amino        group of the triazolophthalazine scaffold, and is cyanomethyl,        or —N(R22)R23, in which    -   R22 and R23 together and with inclusion of the nitrogen atom, to        which they are attached, form a heterocyclic ring Het1, in which    -   Het1 is morpholin-4-yl, or 4N-methyl-piperazin-1-yl.

The compounds according to the invention can be prepared e.g. asdescribed exemplary as follows and according to the following specifiedreaction steps, or, particularly, in a manner as described by way ofexample in the following examples, or analogously or similarly theretoaccording to preparation procedures or synthesis strategies known to theperson skilled in the art.

As shown in reaction scheme 1 below, compounds of formula I, in whichR1, R2 and R3 have the abovementioned meanings can be obtained fromcorresponding compounds of formula II, in which X is a suitable leavinggroup, particularly chlorine, by reaction with corresponding anilinederivatives of formula III.

Said nucleophilic substitution reaction can be carried out as describedin the following examples or as known to the skilled person; thus,depending on the reactivity of the reactants, it can be carried out bymelting the reaction partners without solvent together or by reactingthe reaction partners in a suitable solvent, such as e.g.N,N-dimethylformamide, in the presence of a suitable base, such as e.g.sodium hydride or potassium carbonate, at a temperature to allow thereaction to procedure (this may be e.g., depending on the reactants,ambient temperature, elevated temperature, or reflux temperature of thesolvent used or, under appropriate conditions, beyond it), optionallyunder microwave irradiation.

Compounds of formula III are known, commercially available or can beobtained in a known manner. Compounds of formula II can be obtained asdescribed later herein.

Starting compounds of formula II can be obtained as shown in reactionscheme 4 or as specified in the following examples; or they areart-known, such as e.g. from R. W. Carling et al., J. Med. Chem. Vol.47, No. 7, 1807-1822 (2004), or they can be prepared according to knownprocedures or analogously or similarly to art-described compounds.

Compounds of formula II, in which R1 has the meanings mentioned aboveand X is a suitable leaving group, particularly chlorine, can beobtained from corresponding compounds of formula IV either in one stepby cyclization reaction with corresponding compounds of formulaR1-C(O)Z, in which Z is a suitable leaving group, such as e.g. chlorine;or in two steps via the isolatable intermediate of formula VI, which isaccessible by acylation of compounds of formula IV and which can befurther reacted to desired compounds of formula II by condensationreaction.

Said reactions can be carried out as described in the followingexamples, or under conditions known to the skilled person or analogouslyto art-known reactions similar thereto. Thus, the aforementionedone-step cydization reaction can be carried out similarly as describedin J. Med. Chem. Vol. 31, 1988, p. 1115, in a suitable solvent, such ase.g. toluene, pyridine or dioxane, in the presence of a suitable base(e.g. triethylamine) at elevated temperature or the reflux temperatureof the solvent used.

Compounds of formula IV can be obtained by nucleophilic substitution ofcompounds of formula V, in which X and X′ can be the same and aresuitable leaving groups, particularly X and X′ are both chlorine, andhydrazine.

Compounds of formulae R1-C(O)Z and V are known or can be obtained in aknown manner.

Optionally, compounds of the formula I can be converted into theirsalts, or, optionally, salts of the compounds of the formula I can beconverted into the free compounds.

It is moreover known to the person skilled in the art that if there area number of reactive centers on a starting or intermediate compound itmay be necessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in“Protective Groups in Organic Synthesis” by T. Greene and P. Wuts (JohnWiley & Sons, Inc. 1999, 3^(rd) Ed.) or in “Protecting Groups (ThiemeFoundations Organic Chemistry Series N Group” by P. Kocienski (ThiemeMedical Publishers, 2000).

The substances of formula I according to the invention are isolated andpurified in a manner known per se, for example by distilling off thesolvent under reduced pressure and recrystallizing the residue obtainedfrom a suitable solvent or subjecting it to one of the customarypurification methods, such as, for example, column chromatography on asuitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent(e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutylketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, achlorinated hydrocarbon, such as methylene chloride or chloroform, or alow-molecular-weight aliphatic alcohol, such as ethanol or isopropanol)which contains the desired acid or base, or to which the desired acid orbase is then added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted into thefree compounds, which can in turn be converted into salts, byalkalization or by acidification. In this manner, pharmacologicallyunacceptable salts can be converted into pharmacologically acceptablesalts.

Suitably, the conversions mentioned in this invention can be carried outanalogously or similarly to methods which are familiar per se to theperson skilled in the art.

The person skilled in the art knows on the basis of his/her knowledgeand on the basis of those synthesis routes, which are shown anddescribed within the description of this invention, how to find otherpossible synthesis routes for compounds of formula I. All these otherpossible synthesis routes are also part of this invention.

Having described the invention in detail, the scope of the presentinvention is not limited only to those described characteristics orembodiments. As will be apparent to persons skilled in the art,modifications, analogies, variations, derivations, homologisations andadaptations to the described invention can be made on the base ofart-known knowledge and/or, particularly, on the base of the disclosure(e.g. the explicite, implicite or inherent disclosure) of the presentinvention without departing from the spirit and scope of this inventionas defined by the scope of the appended claims.

The following examples serve to illustrate the invention further withoutrestricting it. Likewise, further compounds of formula I, whosepreparation is not explicitly described, can be prepared in an analogousor similar manner or in a manner familiar per se to the person skilledin the art using customary process techniques.

The compounds of formula I according to the present invention which arementioned in the following examples as final compounds, as well as theirsalts are a preferred subject of the present invention.

In the examples, MS stands for mass spectrum, M for molecular ion inmass spectrometry, m.p. for melting pount, EF for empirical formula, MWfor molecular weight, calc. for calculated, fid. for found, h for hours,and other abbreviations have their meanings customary per se to theskilled person.

EXAMPLES

Final Compounds:

1.(4-Methoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]amine

5.0 g of 6-chloro-3-(4-methoxy-phenyl)[1,2,4]triazolo[3,4-a]phthalazine(compound B1), and 20 g p-anisidine are stirred at 170° C. for 5 h. Thereaction mixture is diluted with 40 ml ethanol and the precipitate isfiltered with suction. The solid is recrystallized fromN,N-dimethylformamide to yield 5.2 g of the title compound. M.p.:301-304° C.

EF: C₂₃H₁₉N₅O₂ (397.44) found: [M+1] 398.2

Alternative Reaction Procedure I:

100 mg 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound B1), 1-3 mmol of the appropriate aniline derivative and 30 mgpotassium carbonate are stirred in 2.5 ml N,N-dimethylformamide at 140°C. for 4 h or at 200° C. for 10 min under microwave irradiation. Thereaction mixture is diluted with dichloromethane/water or sodiumhydroxide solution, the precipitate is filtered with suction, washedwith water and recrystallized from N,N-dimethylformamide.

Alternative Reaction Procedure II:

2.5 mmol of the appropriate aniline derivative and 2.5 mmol sodiumhydride (60%) in 2.5 ml N,N-dimethylformamide are treated with 100 mg6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound B1), at ambient temperature. After 10 min the reaction mixtureis added to water, the precipitate is filtered with suction and thesolid is recrystallized from N,N-dimethylformamide.

Alternative Work Up Procedure:

The product is purified by column chromatography via silica gel.

Starting from the corresponding starting materials described below(compounds B1 to B16) and the appropriate art-known aniline derivatives,the following compounds of Table 1 and further relevant, non-explicitlydescribed similar compounds can be obtained analogously by using one ofthe procedures described above:

TABLE 1 Example No. chemical name EF MW characterization 2.(3,4-Dimethoxy-phenyl)-[3-(4-methoxy- C24 H21 N5 O3 427.47 found:phenyl)-[1,2,4]triazolo[3,4-a]phthalazin- [M + 1] 428.3 6-yl]-amine 3.[3-(4-Methoxy-phenyl)- C22 H17 N5 O 367.41 found:[1,2,4]triazolo[3,4-a]phthalazin-6-yl]- [M + 1] 368.3 phenyl-amine 4.(3-Benzyloxyphenyl)-[3-(4- C29 H23 N5 O2 473.54 m.p.: 260° C.methoxyphenyl)-[1,2,4]triazolo[3,4- a]phthalazin-6-yl]-amine 5.(4-Chlorophenyl)-[3-(4- C22 H16 Cl N5 O 401.86 m.p.: 295° C.methoxyphenyl)-[1,2,4]triazolo[3,4- a]phthalazin-6-yl]-amine 6.(4′-Methoxybiphenyl-4-yl)-[3-(4- C29 H23 N5 O2 473.54 found:methoxyphenyl)-[1,2,4]triazolo[3,4- [M + 1] 474.4a]phthalazin-6-yl]-amine 7. (3-Methoxyphenyl)-[3-(4- C23 H19 N5 O2397.44 found: methoxyphenyl)-[1,2,4]triazolo[3,4- [M + 1] 398.3a]phthalazin-6-yl]-amine 8. [3-(4-Methoxyphenyl)- C28 H21 N5 O2 459.51m.p.: 275.5° C. [1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-phenoxyphenyl)-amine 9. [3-(4-Methoxyphenyl)- C28 H21 N5 O2 459.51found: [1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(3- [M + 1] 460.3phenoxyphenyl)-amine 10. (4-Benzyloxyphenyl)-[3-(4- C29 H23 N5 O2 473.54m.p.: 297° C. methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine 11. [3-(4-Methoxyphenyl)- C23 H19 N5 O 381.44m.p.: 311° C. [1,2,4]triazolo[3,4-a]phthalazin-6-yl]-p- tolyl-amine 12.(4-Ethoxyphenyl)-[3-(4- C24 H21 N5 O2 411.47 m.p.: 297.5° C.methoxyphenyl)-[1,2,4]triazolo[3,4- a]phthalazin-6-yl]-amine 13.[3-(4-Methoxyphenyl)- C26 H24 N6 O2 452.52 m.p.: 314° C.[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4- morpholin-4-yl-phenyl)-amine14. [3-(4-Methoxyphenyl)- C23 H16 F3 N5 O2 451.41 m.p.: 300° C.[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4- trifluoromethoxyphenyl)-amine15. {4-[3-(4-Methoxyphenyl)- C24 H18 N6 O 406.45 m.p.: 295° C.[1,2,4]triazolo[3,4-a]phthalazin-6- ylamino]-phenyl}-acetonitrile 16.[3-(4-Methoxyphenyl)- C23 H19 N5 O S 413.5 m.p.: 326° C.[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4- methylsulfanylphenyl)-amine17. (4-Morpholin-4-yl-phenyl)-[3-(4- C31 H26 N6 O2 514.59 m.p.: 306° C.phenoxyphenyl)-[1,2,4]triazolo[3,4- a]phthalazin-6-yl]-amine 18.[3-(4-Methoxyphenyl)- C27 H27 N7 O 465.56 m.p.: 266° C.[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-[4-(4-methylpiperazin-1-yl)-phenyl]-amine 19.3-[6-(4-Morpholin-4-yl-phenylamino)- C27 H24 N6 O3 480.53 NMR (d₆-DMSO,200 MHz) [1,2,4]triazolo[3,4-a]phthalazin-3-yl]- 3.09-3.17 (m, 4H,2CH₂), benzoic acid methyl ester 3.72-3.83 (m, 4H, 2CH₂), 3.9 (s, 3H,OCH₃), 6.95-7.05 (m, 2H, H^(Ar)), 7.62-7.77 (m, 3H, H^(Ar)), 7.88-8.15(m, 3H, H^(Ar)), 8.5-8.68 (m, 3H, H^(Ar)), 8.9 (s, 1H, H^(Ar)),, 9.29(s, 1H, NH) 20. (4-Morpholin-4-yl-phenyl)-[3-(4- C29 H29 N7 O2 507.6m.p.: 322° C. morpholin-4-yl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]- amine 21. [3-(4-Methoxy-benzyl)-C27 H26 N6 O2 466.55 found: [1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-[M + 1] 467.3 morpholin-4-yl-phenyl)-amine 22.4-[6-(4-Morpholin-4-yl-phenylamino)- C27 H24 N6 O3 480.53 m.p.: 303° C.[1,2,4]triazolo[3,4-a]phthalazin-3-yl]- benzoic acid methyl ester 23.(3-Ethoxyphenyl)-[3-(4- C24 H21 N5 O2 411.47 found:methoxyphenyl-[1,2,4]triazolo[3,4- [M + 1] 412.3a]phthalazin-6-yl]-amine 24. [3-(4-Methoxyphenyl)- C23 H16 F3 N5 O2451.41 found: [1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(3- [M + 1] 452.3trifluoromethoxyphenyl)-amine 25. (4-Morpholin-4-ylphenyl)-(3-phenyl-C25 H22 N6 O 422.49 m.p.: 306° C.[1,2,4]triazolo[3,4-a]phthalazin-6-yl)- amine 26.2-[6-(4-Morpholin-4-yl-phenylamino)- C25 H22 N6 O2 438.49 m.p.: 317° C.[1,2,4]triazolo[3,4-a]phthalazin-3-yl]- phenol 27.(3,5-Dimethoxyphenyl)-[3-(4- C24 H21 N5 O3 427.47 m.p.: 218° C.methoxyphenyl)-[1,2,4]triazolo[3,4- a]phthalazin-6-yl]-amine 28.[3-(1,1-Difluoromethoxy)-phenyl]-[3-(4- C23 H17 F2 N5 O2 433.42 m.p.:247° C. methoxyphenyl)-[1,2,4]triazolo[3,4- a]phthalazin-6-yl]-amine 29.(3,4-Diethoxyphenyl)-[3-(4- C26 H25 N5 O3 455.52 m.p.: 242.5° C.methoxyphenyl)-[1,2,4]triazolo[3,4- a]phthalazin-6-yl]-amine 30.[4-(1,1-Difluoromethoxy)-phenyl]-[3-(4- C23 H17 F2 N5 O2 433.42 m.p.:294° C. methoxyphenyl)-[1,2,4]triazolo[3,4- a]phthalazin-6-yl]-amine 31.(4-Bromo-phenyl)-[3-(4-methoxy- C22 H16 Br N5 O 446.31 m.p.: 314-316° C.phenyl)-[1,2,4]triazolo[3,4-a]phthalazin- 6-yl]-amine

Starting Compounds

B1. 6-Chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

6.0 g (4-chloro-phthalazin-1-yl)hydrazine (compound C1) are suspended ina mixture of 160 ml toluene and 18 ml triethylamine at 60° C. andtreated with a solution of 6.0 g 4-methoxy-benzoyl chloride in 48 mltoluene. The mixture is stirred at 110° C. for 6 h, cooled to ambienttemperature, filtered with suction and rinsed with toluene. The solid isrecrystallized from N,N-dimethylformamide, the precipitate is washedwith water and dried to yield 5.2 g of the title compound (m.p.:192-193° C.). EF: C₁₆H₁₁ClN₄O (310.75) found: [M+1] 311.2

Alternative Work Up Procedure:

The products can be purified by column chromatography via silica gel.

Starting from (4-chloro-phthalazin-1-yl)-hydrazine (compound C1) and theappropriate benzoic acid derivatives, the following compounds B2 to B15can be obtained analogously to the procedure as described for compoundB1 or B16.

B2. 6-Chloro-3-(2-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

EF: C₁₈H₁₁ClN₄O (310.75) found: [M+1] 311.3

m.p.: 136-140° C.

B3. 6-Chloro-3-(2-fluoro-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

EF: C₁₅H₈ClF N₄ (298.71) found: [M+1] 299.0

m.p.: 185-188° C.

B4. 6-Chloro-3-(2-bromo-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

EF: C₁₅H₈BrCl N₄ (359.61) found: [M+1] 358.8

m.p.: 197-200° C.

B5.6-Chloro-3-(2-trifluoromethyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

EF: C₁₈H₈ClF₃N₄ (348.72) found: [M+1] 348.9

m.p.: 225-228° C.

B6. 6-Chloro-3-(2-methyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

m.p.: 189-191° C.

B7. 6-Chloro-3-(4-bromo-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

EF: C₁₅H₈BrClN₄ (359.61) found: [M+1] 358.8

m.p.: 191-195° C.

B8.6-Chloro-3-(2-N,N-dimethylamino-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

EF: C₁₇H₁₄ClN₅ (323.79) found: [M+1] 324.0

m.p.: 180-185° C.

B9. 6-Chloro-3-(4-methoxybenzyl)-[1,2,4]triazolo[3,4-a]phthalazine

EF: C₁₇H₁₃ClN₄O (324.77) m.p.: 219.5° C.

B10. 4-(6-Chloro-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)-benzoic acidmethyl ester

EF: C17H11ClN4O2 (338.76) m.p.: 211° C.

m.p.: 210-211° C.

B11. 6-Chloro-3-(3-phenoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

C21H13ClN4 O (372.82) m.p.: 102° C.

B12. 3-(6-Chloro-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)-benzoic acidmethyl ester

C17H11ClN4O2 (338.76) found: [M+1] 339.3

B13. 2-(6-Chloro-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)-phenol

C15H9ClN4O (296.72) found: [M+1] 297.4

B14. 3-(6-Chloro-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)-phenol

C15H9ClN4O (296.72) found: [M+1] 297.3

B15.6-Chloro-3-(4-morpholin-4-yl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

C19H16ClN5O (365.83) m.p.: 286° C.

B16. 6-Chloro-3-phenyl-[1,2,4]triazolo[3,4-a]phthalazine

Step1:

2.5 g (4-chloro-phthalazin-1-yl)-hydrazine (compound C1) are suspendedin 250 ml toluene and treated with a solution of 1.7 ml benzoic acidchloride in 50 ml toluene at reflux temperature. After 2 h the reactionmixture is cooled to ambient temperature and filtered with suction. Thefiltrate is concentrated under reduced pressure and the residue isrecrystallized from N,N-dimethylformamide to yield 1.2 g of benzoic acid(4-chloro-2H-phthalazin-1-ylidene)-hydrazide.

EF: C₁₅H₁₁ClN₄O (298.73) found: [M+1] 299.1

Step 2:

2.5 g benzoic acid (4-chloro-2H-phthalazin-1-ylidene)-hydrazide and 1 gtriethylamine hydrochloride are suspended in 60 ml ethylene glycol andstirred at 130° C. for 3 h. The reaction mixture is cooled to ambienttemperature and added to 600 ml water. The product is extracted withdichloromethane, the organic layer is dried with sodium sulphate andconcentrated under reduced pressure. The residue is recrystallized fromN,N-dimethylformamide to give the title compound.

EF: C15H9ClN4 (280.72) found: [M+1] 281.2

m.p.: 162° C.

Alternative work up procedure: The products can be purified by columnchromatography via silica gel.

C1. (4-Chloro-phthalazin-1-yl)-hydrazine

10 g commercially available dichlorophthalazine are added portionwise at90° C. to a solution of 50 ml ethanol and 20 ml hydrazine hydrate. After10 min the reaction mixture is cooled to ambient temperature, theprecipitate is filtered with suction and rinsed with ethanol to yield8.4 g of the title compound.

EF: C8H7ClN4 (194.62) found: [M+1] 195.0

Commercial Applicability

The compounds according to the invention have useful pharmacologicalproperties which make them industrially utilizable. As selectiveinhibitors of cyclic GMP-hydrolysing phosphodiesterases (cGMP-PDEinhibitors)—preferentially of type 2-, they are suitable on the one handas therapeutics for conditions of pathologically enhanced endothelialactivity and impaired endothelial barrier function such as septic shock,vascular edema, or diseases associated with unwanted neoangiogenesis. Onthe other hand, given the expression of PDE2 in neuronal tissue thecompounds may also be useful in neurodegenerative conditions. Inaddition, PDE2 is expressed in human platelets and PDE2 inhibitors wereshown to suppress platelet functions. In consequence, the compounds maybe used as anti-thrombotics/platelet aggregation inhibitors.Furthermore, since PDE2 was shown in myocardium the compounds may afforda potential to protect against arrhythmias.

On account of their cGMP-PDE (preferentially PDE2) inhibitingproperties, the compounds according to the invention can be employed inhuman and veterinary medicine as therapeutics, where they can be used,for example, for the treatment and prophylaxis of the followingillnesses: (1) all conditions of pathologically enhanced endothelialactivity/impaired endothelial barrier function such as multi-organfailure in particular acute respiratory distress syndrome (ARDS) inseptic shock, pneumonia, acute and chronic airway disorders of varyingorigin (rhinitis, bronchitis, bronchial asthma, emphysema, COPD),angioedema, peripheral edema, cerebral edema for example traumatic orfollowing stroke; (2) all conditions associated with pathologicallyenhanced neoangiogenesis such as all kinds of tumors (benign ormalignant) which are associated with neoangiogenesis and all kinds ofinflammatory diseases associated with neoangiogenesis for exampledisorders of the arthritis type (rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis and other arthritic conditions), all formsof psoriasis, retinal blindness, bronchial asthma, inflammatory boweldisease, transplant rejection, allograft rejections, atherosclerosis;(3) all conditions for which platelet aggregation inhibition inconjunction with reduction of enhanced endothelial activation isdesirable such as thrombembolic disorders and ischaemias coveringmyocardial infarct, cerebral infarct, transitory ischaemic attacks,angina pectoris, peripheral circulatory disorders, prevention ofrestenosis after thrombolysis therapy, percutaneous translumialangioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA)and bypass; (4) all types of impaired cognition in particular cognitivedisorders such as mild cognitive disorder (MCI), Alzheimer's disease,Lewy-Body dementia, Parkinson's disease and cerebrovascular dementia;(5) in cardiac arrhythmias, and (6) osteoporosis, bone fracture and/ordefect, bone in-growth.

The invention further relates to a method for the treatment of mammals,including humans, which are suffering from one of the above mentionedillnesses. The method is characterized in that a therapeutically activeand pharmacologically effective and tolerable amount of one or more ofthe compounds according to the invention is administered to the illmammal.

The invention further relates to a method for inhibiting PDE,particularly PDE2, comprising contacting said PDE with an effectiveamount of a compound according to the invention.

The invention further relates to a method for inhibiting PDE,particularly PDE2, comprising administering a pharmacologically activeand therapeutically effective and tolerable amount of at least onecompound according to the invention to a mammal in need of suchinhibition.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses,especially the illnesses mentioned.

The invention further relates to the compounds according to theinvention having PDE, particularly PDE2, inhibitory activity.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions which areemployed for the treatment and/or prophylaxis of the illnessesmentioned.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions which areemployed for the treatment and/or prophylaxis of PDE-, particularlyPDE2-, associated diseases.

The invention furthermore relates to pharmaceutical compositions for thetreatment and/or prophylaxis of the illnesses mentioned, which containone or more of the compounds according to the invention.

The invention moreover relates to pharmaceutical compositions havingPDE, particularly PDE2, inhibitory activity.

Additionally, the invention relates to an article of manufacture, whichcomprises packaging material and a pharmaceutical agent contained withinsaid packaging material, wherein the pharmaceutical agent istherapeutically effective for antagonizing the effects of the cyclicnucleotide phosphodiesterase of type 2 (PDE2), ameliorating the symptomsof an PDE2-mediated disorder, and wherein the packaging materialcomprises a label or package insert which indicates that thepharmaceutical agent is useful for preventing or treating PDE2-mediateddisorders, and wherein said pharmaceutical agent comprises one or morecompounds of formula 1 according to the invention. The packagingmaterial, label and package insert otherwise parallel or resemble whatis generally regarded as standard packaging material, labels and packageinserts for pharmaceuticals having related utilities.

The administration of the pharmaceutical compositions according to theinvention may be performed in any of the generally accepted modes ofadministration available in the art. Illustrative examples of suitablemodes of administration include intravenous, oral, nasal, parenteral,topical, transdermal and rectal delivery. Intravenous and oral deliveryis preferred.

The pharmaceutical compositions are prepared by processes which areknown per se and familiar to the person skilled in the art. Aspharmaceutical compositions, the compounds according to the invention(=active compounds) are either employed as such, or preferably incombination with suitable pharmaceutical auxiliaries and/or excipients,e.g. in the form of tablets, coated tablets, capsules, caplets,suppositories, patches (e.g. as TTS), emulsions, suspensions, gels orsolutions, the active compound content advantageously being between 0.1and 95% and where, by the appropriate choice of the auxiliaries and/orexcipients, a pharmaceutical administration form (e.g. a delayed releaseform or an enteric form) exactly suited to the active compound and/or tothe desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries or excipientswhich are suitable for the desired pharmaceutical formulations onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents or permeation promoters, canbe used.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

For the treatment of skin diseases, the compounds according to theinvention are in particular administered in the form of thosepharmaceutical compositions which are suitable for topical application.For the production of the pharmaceutical compositions, the compoundsaccording to the invention (=active compounds) are preferably mixed withsuitable pharmaceutical auxiliaries and further processed to givesuitable pharmaceutical formulations. Suitable pharmaceuticalformulations are, for example, powders, emulsions, suspensions, sprays,oils, ointments, fatty ointments, creams, pastes, gels or solutions.

The pharmaceutical compositions according to the invention are preparedby processes known per se. The dosage of the active compounds is carriedout in the order of magnitude customary for PDE inhibitors. Topicalapplication forms (such as ointments) for the treatment of dermatosesthus contain the active compounds in a concentration of, for example,0.1-99%. The dose for administration by inhalation is customarly between0.1 and 3 mg per day. The customary dose in the case of systemic therapy(p.o. or i.v.) is between 0.03 and 3 mg/kg per day.

Biological Investigations

Method for Measuring Inhibition of PDEs Activities

Abbreviations:

PDE: phosphodiesterase, PCR: polymerase chain reaction, RT-PCR: reversetranscription-polymerase chain reaction, dNTPs: deoxynucleosidetriphosphates, RNA: ribonucleic acid , cDNA: complementarydeoxyribonucleic acid, bp: basepairs, (dT)₁₅: pentadecathymidylic acid,ORF: open reading frame, GB no.: GenBank database accession number, rBV:recombinant baculovirus, wt: wild type, aa: aminoacid, UCR: upstreamconserved region, PM: polyacrylamide.

Aminoacids are abbreviated with the 1-character symbol: A for alanine, Cfor cysteine, D for aspartic acid, E for glutamic acid, F forphenylalanine, G for glycine, H for histidine, I for isoleucine, K forlysine, L for leucine, M for methionine, N for asparagine, P forproline, Q for glutamine, R for arginine, S for serine, T for threonine,V for valine, W for tryptophane, Y for tyrosine.

General Methods for Cloning Recombinant PDEs

RNA was purified from cell lines using the RNeasy Mini Kit from Qiagen.1 μg RNA was reverse transcribed into single-stranded cDNA in a 20 μlreaction using Expand Reverse Transcriptase (Roche) with 50 pM of primer(dT)₁₅ and 1 mM dNTPs (both from Roche). 5 μl of cDNA were used astemplate for the subsequent PCR reaction. Human cDNAs from tissues werepurchased from Clontech or Invitrogen. 1 μl was used for PCR reaction.

PCR was carried out in a Stratagene Robocycler 40 or in a MWG Primus 96plus thermocycler. Typically, PCR was carried out with the Expand LondTemplate PCR System from Roche in buffer 3 plus 0.75 mM MgCl₂, 0.3 μMeach primer, 500 μM dNTPs.

PCR products were purified with the High Pure PCR Product PurificationKit (Roche) or from agarose gel with the QIAquick Gel Extraction kitfrom Qiagen, and cloned into the pCR2.1-TOPO vector from Invitrogen. TheORFs were subcloned in baculovirus expression vectors (transferplasmids). The pCR-Bac and pVL vectors were from Invitrogen. The pBacPakvectors (pBP8 or pBP9) were from Clontech. Restriction endonucleaseswere from Roche and MBI Fermentas. Modifying enzymes and T4 DNA ligasewere from New England Biolabs. DNA was sequenced by the company GATCGmbH (Konstanz, Germany, www.gatc.de) or in ALTANA Pharma's lab using anABI PRISM 310 and the Big dye terminator cycle sequencing v2 chemistry(Applied Biosystem). Sequence analysis was performed with HitachiSoftware DNASIS Version 2.5 or with Vector NTI 7. When necessary, invitro mutagenesis was eventually performed with the QuickChangeSite-Directed Mutagenesis Kit from Stratagene.

Cloning of Human PDE 2A3

The PDE2A3 (GB no. U67733) was amplified in 2 steps using PCR from braincDNA. A N-terminal fragment was isolated using primers CP1PD2AS(5′-GAGGAGTGATGGGGCAGGC-3′) and PR9PD2AA (5′-GCGAAGTGGGAGACAGAAAAG-3′),a C-terminal fragment was isolated using primers PR7PD2AS(5′-GATCCTGAACATCCCTGACG-3′) and CP3PD2AA (5′-GGGATCACTCAGCATCAAGGC-3′).The PCR products were cloned into the vector pCR2.1-Topo. The N-terminalfragment was first subcloned with EcoRI into pBluescript II KS (−),afterwards a Bst1107I/EcoRV fragment was exchanged with thecorresponding restriction fragment from the C-terminal clone, to obtaina complete ORF. The ORF for the PDE2A3 was subcloned into pBP8 usingXbal and Kpnl.

Expression of Recombinant PDE2

The rBV was prepared by means of homologous recombination in Sf9 insectcells. The expression plasmids were cotransfected with Bac-N-Blue(Invitrogen) or Baculo-Gold DNA (Pharmingen) using a standard protocol(Pharmingen). Wt virus-free recombinant virus supernatants were selectedusing plaque assay methods. After that, high-titre virus supernatantswere prepared by amplifying 3 times. PDE2 was expressed in Sf21 cells byinfecting 2×10⁶ cells/ml with an MOI (multiplicity of infection) between1 and 10 in serum-free SF900 medium (Life Technologies). Cells werecultured at 28° C., typically for 48 hours, after which they werepelleted for 5-10 min at 1000 g and 4° C. In spinner flasks, cells werecultured at a rotational speed of 75 rpm. The SF21 insect cells wereresuspended, at a concentration of approx. 10⁷ cells/ml, in ice-cold (4°C.) homogenization buffer (20 mM Tris, pH 8.2, containing the followingadditions: 140 mM NaCl, 3.8 mM KCl, 1 mM EGTA, 1 mM MgCl₂, 1 mMβ-mercaptoethanol, 2 mM benzamidine, 0.4 mM Pefablock, 10 μM leupeptin,10 μM pepstatin A, 5 μM trypsin inhibitor) and disrupted byultrasonication. The homogenate was then centrifuged for 10 min at1000×g and the supernatant was stored at −80° C. until subsequent use(see below). The protein content was determined by the Bradford method(BioRad, Munich) using BSA as standard. Integrity and size ofrecombinant proteins were analysed by western blot.

Measurement of Recombinant Human PDE2A3 Inhibition by SPA Technology

Recombinant human PDE2A3 activities were inhibited by the test samplesin a modified SPA (scintillation proximity assay) test, supplied byAmersham Pharmacia Biotech (see procedural instructions“phosphodiesterase [3H]cAMP SPA enzyme assay, code TRKQ 7090”), carriedout in 96-well microtitre plates (MTP's). The test volume is 100 μl andcontains 20 mM Tris buffer (pH 7.4), 0.1 mg of BSA (bovine serumalbumin)/ml, 5 mM Mg²⁺, 0.5 μM cAMP (including about 50,000 cpm of[3H]cAMP), 5 μM cGMP (to activate PDE2A3), 2 μl of the respectivesubstance dilution in DMSO and sufficient recombinant PDE (1000×gsupernatant, see above) to ensure that 15-20% of the CAMP is convertedunder the said experimental conditions. After a preincubation of 5 minat 37° C., the reaction is started by adding the substrate (cAMP) andthe assays are incubated for a further 15 min; after that, they arestopped by adding SPA beads (50 μl ). In accordance with themanufacturer's instructions, the SPA beads had previously beenresuspended in water and then diluted 1:3 (v/v); the diluted solutionalso contains 3 mM IBMX. After the beads have been sedimented (>30 min),the MTP's are analyzed in commercially available measuring appliancesand the corresponding IC₅₀ values of the compounds for the inhibition ofPDE activities are determined from the concentration-effect curves bymeans of non-linear regression.

Method to Assess Inhibition of Macromolecule Permeability of HUVECMonolayers

The procedure to measure macromolecule permeability of endothelial cellmonolayers followed the method described by Langeler & van Hinsbergh(1988) with modifications. Human umbilical vein endothelial cells wereisolated from umbilical cords according to standard procedures (Jaffe etal. 1973) and cultured in endothelial cell basal medium (EBM)supplemented with 2% FCS, 0.5 ng/ml VEGF, 10 ng/ml bFGF, 5 ng/ml EGF, 20ng/ml Long R3 IGF-1, 0.2 μg/ml hydrocortisone, 1 μg/ml ascorbic acid,22.5 μg/ml heparin, 50 μg/ml gentamicin, 50 ng/ml amphotericin B (EGM2purchased from Promocell GmbH, Heidelberg, Germany). At confluency,cells were trypsinized and replated at 73000 cells per well on 3 μmpolycarbonate filter Transwell inserts (Costar GmbH, Bodenheim, Germany)precoated with 10 μg cm² ⁻¹ Fibronectin (Sigma, Taufkirchen, Germany).HUVECs were cultured in EGM2 (100 μl in the upper wells and 600 μl inthe lower wells) over four days prior the experiments and medium waschanged every other day. At the day of the experiment culture medium wasreplaced by M199 with 1% human serum albumin. Endothelial cells werepreincubated with cyclic nucleotide modifiers (the selective PDE3inhibitor motapizone, the selective PDE4 inhibitor RP73401, the cGMPgenerators ANP or SNP and PDE2 inhibitors) for 15 min. HUVECs were thenstimulated with Thrombin (1 U ml⁻¹) (Sigma, Taufkichen, Germany) andhorsh radish peroxidase (5 μg/ml) (Sigma, Taufkirchen, Germany) as themacromolecule marker protein was added to the upper wells. Following 1 hincubation time Transwells were removed and the activity of horsh radishperoxidase that penetrated the endothelial cell monolayer was measuredin the lower wells with the 3,3′,5,5′-tetramethylbenzidine liquidsubstrate system from Sigma (Taufkirchen, Germany).

Results

Representative inhibitory values [measured as −log IC₅₀ (mol/l)]determined in the aforementioned assay follow from the following tableA, in which the numbers of the compounds correspond to the numbers ofthe examples.

TABLE A Inhibition of PDE2 activity Compound -log IC₅₀ [mol/l] 1 to 19,and 21 to 30 The inhibitory values of these listed compounds lie in therange from 7.4 to 9.1

In parallel, compounds according to the invention can inhibitThrombin-induced permeability of HUVEC monolayers for horsh radishperoxidase (HRP) as a macromolecule marker. Therefore, PDE2 inhibitorsare suggested to improve the endothelial barrier function, which isimpaired in numerous conditions such as acute respiratory distresssyndrome (ARDS) or severe pneumonia. The system to measure thesecellular effects of the PDE2 inhibitors observed the enzymologicalcharacteristics of PDE2 which exhibits a rather high Km for cAMP and theactivity of which is activated by cGMP. The Thrombin-induced increase ofHRP permeability was completely abolished by complete inhibition of PDE3(10 μM Motapizone) and PDE4 (1 μM RP73401). However, in the additionalpresence of ANP (100 nM) or SNP (1 mM) to augment cGMP the inhibition byPDE3 and 4 inhibition of permeability was partially reversed. PDE2inhibitors blocked the thrombin-stimulated HRP-permeability if 1 μMRP73401, 10 μM Motapizone, 100 nM ANP or 1 mM SNP were presentindicating that ANP or SNP by generating cGMP activate PDE2. Theconcentration-dependent inhibition of HRP permeability at differentconcentrations was assessed from the percent inhibition in the presenceand absence of the PDE2 inhibitors and in the presence of 1 μM RP73401,10 μM Motapizone and 100 nM ANP. In the absence of PDE3 and 4inhibition, ANP or SNP the PDE2 inhibitors showed very little effect inThrombin-induced macromolecule hyperpermeability.

Inhibition of SNP- or ANP-Induced Permeability of HUVEC Monolayers:

HUVEC cells on 3 μm polycarbonate filters (Transwells) were preincubatedwith 1 μM RP73401 (to block PDE4) and 10 μM Motapizone (to block PDE3),1 mM SNP or 100 nM ANP and test sample over 15 min and then stimulatedwith 1 U/ml thrombin. HRP passage into the lower wells was assessedafter 60 min. RP73401 and Motapizone completely blocked thrombin-inducedhyperpermeability, which was partially reversed by SNP and ANP.

Compounds according to this invention can inhibit the SNP- orANP-induced permeability increase in a concentration-dependent fashion.

Representative inhibitory values [measured as −log IC₅₀ (mol/l)]determined in the aforementioned assay follow from the following tableB, in which the numbers of the compounds correspond to the numbers ofthe examples.

TABLE B Inhibition of SNP- or ANP-induced permeability Compound -logIC₅₀ [mol/l] 2, 6 to 19, and 23 to 30 The inhibitory values of theselisted compounds lie in the range from 6.5 to 8.1

1-11. (canceled)
 12. A method for treating an acute or chronic airwaydisorder in a patient in need thereof, comprising administering to saidpatient a therapeutically effective amount of a compound of formula I

in which R1 is —U-A, in which U is a direct bond, or methylene (—CH₂—),A is phenyl, pyridinyl, thienyl or R11- and/or R111-substituted phenyl,in which R11 is 1-4C-alkyl, halogen, trifluoromethyl, hydroxyl,1-4C-alkoxy, completely or predominantly fluorine-substituted1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl, morpholino, ordi-1-4C-alkylamino, R111 is 1-4C-alkoxy, halogen, hydroxyl, or1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, phenyl-1-4C-alkoxy,phenoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, halogen,trifluoromethyl, nitro, phenyl, R21-substituted phenyl, completely orpredominantly fluorine-substituted 1-4C-alkoxy, 1-4C-alkylthio,cyano-1-4C-alkyl, or —N(R22)R23, in which R21 is 1-4C-alkoxy, halogen or1-4C-alkyl, R22 and R23 together and with inclusion of the nitrogenatom, to which they are attached, form a heterocyclic ring Het1, inwhich Het1 is optionally substituted by R24, and is a 3- to 7-memberedmonocyclic fully saturated heterocyclic ring radical comprising thenitrogen atom, to which R22 and R23 are bonded, and optionally onefurther heteroatom selected from the group consisting of nitrogen,oxygen and sulphur, in which R24 is 1-4C-alkyl, R3 is hydrogen,1-4C-alkyl, 1-4C-alkoxy or halogen, or a pharmaceutically acceptablesalt thereof.
 13. The method of claim 12, wherein the acute or chronicairway disorder is selected from the group consisting of acuterespiratory distress syndrome (ARDS) in septic shock, pneumonia,rhinitis, bronchitis, bronchial asthma, emphysema and chronicobstructive pulmonary disease (COPD).
 14. The method of claim 12,wherein the acute or chronic airway disorder is selected from the groupconsisting of pneumonia and acute respiratory distress syndrome (ARDS)in septic shock.
 15. The method of claim 12, wherein, in the compound offormula I, R1 is —U-A, in which U is a direct bond, or methylene(—CH₂—), A is phenyl, pyridinyl, thienyl, dimethoxyphenyl, orR11-substituted phenyl, in which R11 is methyl, tert-butyl, chlorine,fluorine, bromine, trifluoromethyl, hydroxyl, methoxy, ethoxy,trifluoromethoxy, phenoxy, methoxycarbonyl, morpholino, ordimethylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy,phenyl-1-4C-alkoxy, phenoxy, halogen, phenyl, R21-substituted phenyl,completely or predominantly fluorine-substituted 1-4C-alkoxy,1-4C-alkylthio, cyano-1-4C-alkyl, or —N(R22)R23, in which R21 is1-4C-alkoxy, R22 and R23 together and with inclusion of the nitrogenatom, to which they are attached, form a heterocyclic ring Het1, inwhich Het1 is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, or 4N-(1-4C-alkyl)-piperazin-1-yl, R3 is hydrogen or1-4C-alkoxy, or a pharmaceutically acceptable salt thereof.
 16. Themethod of claim 12, wherein, in the compound of formula I, R1 is —U-A,in which U is a direct bond, or methylene (—CH₂—), A is phenyl,4-methoxy-phenyl, 2-methoxy-phenyl, 2-hydroxy-phenyl, 2-bromo-phenyl,4-bromo-phenyl, 2-fluoro-phenyl, 2-(trifluoromethyl)-phenyl,2-methyl-phenyl, 3-methoxy-phenyl, 3-bromo-phenyl, 3-fluoro-phenyl,2-dimethylamino-phenyl, methoxycarbonyl, phenoxy, or3-(trifluoromethyl)-phenyl, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy,phenyl-1-4C-alkoxy, phenoxy, halogen, phenyl, R21-substituted phenyl,completely or predominantly fluorine-substituted 1-4C-alkoxy,1-4C-alkylthio, cyano-1-4C-alkyl, or —N(R22)R23, in which R21 is1-4C-alkoxy, R22 and R23 together and with inclusion of the nitrogenatom, to which they are attached, form a heterocyclic ring Het1, inwhich Het1 is morpholin-4-yl, or 4N-(1-4C-alkyl)-piperazin-1-yl, R3 ishydrogen or 1-4C-alkoxy, or a pharmaceutically acceptable salt thereof.17. The method of claim 12, wherein, in the compound of formula I, R1 is4-methoxy-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 2-bromo-phenyl,3-bromo-phenyl, 4-bromo-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl,2-(trifluoromethyl)-phenyl, or 3-(trifluoromethyl)-phenyl; R2 ishydrogen, methyl, methoxy, ethoxy, benzyloxy, chlorine, phenoxy, phenyl,4-methoxy-phenyl, trifluoromethoxy, difluoromethoxy, methylthio,cyanomethyl, or —N(R22)R23, in which R22 and R23 together and withinclusion of the nitrogen atom, to which they are attached, form aheterocyclic ring Het1, in which Het1 is morpholin-4-yl, or4N-methyl-piperazin-1-yl, R3 is hydrogen, methoxy or ethoxy, or apharmaceutically acceptable salt thereof.
 18. The method of claim 12,wherein the compound of formula I is selected from the group consistingof:(4-Methoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,(3,4-Dimethoxy-phenyl)-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-phenyl-amine,(3-Benzyloxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,(4-Chlorophenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,(4′-Methoxybiphenyl-4-yl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,(3-Methoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-phenoxyphenyl)-amine,[3-(4-Methoxyphenyl)-]1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(3-phenoxyphenyl)-amine,(4-Benzyloxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-p-tolyl-amine,(4-Ethoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-morpholin-4-yl-phenyl)-amine,[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-trifluoromethoxyphenyl)-amine,{4-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetonitrile,[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-methylsulfanylphenyl)-amine,(4-Morpholin-4-yl-phenyl)-[3-(4-phenoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-[4-(4-methylpiperazin-1-yl)-phenyl]-amine,3-[6-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-benzoicacid methyl ester,(4-Morpholin-4-yl-phenyl)-[3-(4-morpholin-4-yl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,[3-(4-Methoxy-benzyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-morpholin-4-yl-phenyl)-amine,4-[6-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-benzoicacid methyl ester,(3-Ethoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(3-trifluoromethoxyphenyl)-amine,(4-Morpholin-4-ylphenyl)-(3-phenyl-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)-amine,2-[6-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-phenol,(3,5-Dimethoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,[3-(1,1-Difluoromethoxy)-phenyl]-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,(3,4-Diethoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,[4-(1,1-Difluoromethoxy)-phenyl]-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,(4-Bromo-phenyl)-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,and the pharmaceutically acceptable salts of these compounds.